Pharmaceutically Acceptable Salts and Polymorphic Forms of Hydrocodone Benzoic Acid Enol Ester and Processes for Making Same

ABSTRACT

Compositions comprising hydrocodone benzoic acid enol ester to form novel prodrugs including hydrocodone benzoic acid enol ester salts, and various polymorphs. Also provided are processes for the preparation of hydrocodone benzoic acid enol ester salts, and various polymorphs.

FIELD OF THE INVENTION

The present disclosure relates to pharmaceutically acceptable salts andpolymorphic forms of hydrocodone benzoic acid enol ester. The disclosurefurther relates to processes for making the salts and polymorphic formsof hydrocodone benzoic acid enol ester.

BACKGROUND OF THE INVENTION

Hydrocodone benzoic acid enol ester is an opiate prodrug that is usefulfor overdose prevention. Previous processes for the preparation ofhydrocodone benzoic acid enol esters require the isolation of purehydrocodone from hydrocodone bitartrate before preparation of thebenzoic acid enol ester. Such processes are inefficient and expensive.Another drawback to prior art processes is the difficulty in preparing ahigh quality product. Thus, there remains a need for new processes formaking hydrocodone benzoic acid enol esters.

SUMMARY OF THE INVENTION

In one embodiment, the present disclosure provides a substantially purecompound comprising hydrocodone benzoic acid enol ester having a levelof impurities less than about 10% to 0.1%. For example, the impuritiescan be, for example, less than 10% (purity of 90%), less than 5% (purityof 95%), less than 2.0% (purity of 98%), less than 1.0% (purity of99%/), less than 0.5% (purity of 99.5%), less than 0.1% (purity of99.9%). In one aspect of this embodiment, the level of impurities isless than 0.1%. In another aspect of this embodiment, the impuritiesinclude hydrocodone and benzoic acid.

In another embodiment, the compound may be part of a pharmaceuticalcomposition, such as but not limited to any pharmaceutically acceptablesalt of hydrocodone benzoic acid enol ester. According to this aspect,the pharmaceutically acceptable salt may be selected from the groupconsisting of hydrochloride, hydrobromide, hydrogensulphate, sulphate,maleate, fumarate, oxalate, methanesulfonate, succinate, ascorbate, andtartrate. However, other suitable salts can be used as would be known byone of ordinary skill in the art. Other embodiments of the inventionfurther include polymorphic forms of hydrocodone benzoic acid enol esterhydrochloride such as Forms I, II, III, IV, V, or a combination thereof.In yet another embodiment, a pharmaceutical composition may comprise apolymorphic form of hydrocodone benzoic acid enol ester hydrochloride,such as Form I, II, III, IV, V, or a combination thereof.

In accordance with other embodiments, various polymorphic forms ofhydrocodone benzoic acid enol ester hydrochloride are described. Thepolymorphic form may be one of Form I, II. III, IV, or V, oralternatively may be a combination thereof.

In some embodiments, polymorphic Form I can have an XRPD pattern havingXRPD peaks at about the following 2θ values: 6.16, 9.05, 10.95, 11.91,12.32, 13.16, 14.60, 14.94, 17.04, 17.23, 17.80, 18.57, 19.18, 20.66,21.10, 22.15, 23.50, 26.07, and 28.39. Polymorphic Form II can have anXRPD pattern having XRPD peaks at about the following 2θ values: 4.31,8.62, 12.95, 13.19, 13.42, 14.33, 14.97, 15.72, 17.48, 18.47, 21.73,22.92, 24.15, 24.98, 26.41, 26.53, 26.62, 27.93, and 30.46. PolymorphicForm III can have an XRPD pattern having XRPD peaks at about thefollowing 2θ values: 4.35, 8.68, 13.01, 13.27, 13.86, 14.06, 15.05,16.02, 18.40, 21.72, 22.38, and 26.14. Polymorphic Form IV can have anXRPD pattern having XRPD peaks at about the following 2θ values: 7.87,10.27, 11.87, 12.56, 13.18, 14.19, 15.34, 16.77, 17.67, 18.58, 19.50,20.30, and 21.31. Polymorphic Form V can have an XRPD pattern havingXRPD peaks at about the following 2θ values: 6.17, 7.50, 9.04, 10.96,11.93, 12.34, 12.64, 13.13, 14.34, 14.62, 14.93, 16.73, 17.04, 17.22,17.81, 18.59, 18.98, 19.19, 19.52, 20.67, 21.10, 21.91, 22.15, 22.82,23.49, 25.03, 25.37, 26.09, and 26.43.

In another aspect, a solid pharmaceutical composition comprising atherapeutically effective amount of one or more polymorphic forms ofhydrocodone benzoic acid enol ester hydrochloride and a pharmaceuticallyacceptable excipient in a formulation for administration is provided. Inone embodiment, the formulation can be designed for oral administration.Accordingly, the solid pharmaceutical composition can be a coated oruncoated tablet, a hard or soft gelatin capsule, a sugar-coated pill, alozenge, a wafer sheet, a pellet, or a powder. As would be appreciatedby one of ordinary skill in the art, however, formulations comprisingtherapeutically effective amounts of the polymorphic forms disclosedherein may also be designed for other routes of administration. In oneaspect of this embodiment, the composition may consist of a purepolymorphic form.

In another aspect, the disclosed subject matter is directed to a processfor preparing polymorphic forms of hydrocodone benzoic acid enol esterhydrochloride. In one embodiment, hydrocodone benzoic acid enol esterhydrochloride is prepared by recrystallizing hydrocodone benzoic acidenol ester hydrochloride from an organic solvent in the presence ofwater. In one embodiment, the process produces polymorphic Form I. Forexample, polymorphic Form I is formed in instances where the molar ratioof water to hydrocodone benzoic acid enol ester hydrochloride is atleast about 0.5, such as about 0.5, 1.0, or more.

In accordance with the process, the organic solvent may be an alcohol,an ether, or ester. For example, the solvent can be selected fromethanol, tert-butyl methyl ether, or ethyl acetate, or a combinationthereof.

In another embodiment, the hydrocodone benzoic acid enol esterhydrochloride is recrystallized in an organic solvent containing lessthan 0.2% water to form polymorphic Form II. The organic solvent may beanhydrous. For example, the solvent may be isopropanol, isopropylacetate, or a mixture of the two.

In yet another embodiment, polymorphic Form II can be employed to formpolymorphic forms III, IV, and V. For example, hydrocodone benzoic acidenol ester hydrochloride Form II can be heated at a temperature ofbetween about 210° C. and about 230° C. to create polymorphic Form III.In another embodiment, hydrocodone benzoic acid enol ester hydrochlorideForm II can be exposed to a high relative humidity for a period of timeto create Form IV. In one embodiment, the relative humidity is fromabout 75% to about 100%. Hydrocodone benzoic acid enol esterhydrochloride Form III can be exposed to a high relative humidity for aperiod of time to create Form V. The relative humidity may be betweenabout 75% and about 100%.

In yet another aspect of the present embodiment, hydrocodone benzoicacid enol ester hydrochloride is prepared in an amorphous form. Thisform may be prepared by dissolving the hydrocodone benzoic acid enolester hydrochloride in an organic solvent, then evaporating the solvent.

In another embodiment, a process of preparing hydrocodone benzoic acidenol ester is provided. The process includes heating hydrocodone freebase with a benzoylating reagent with or without the presence of a baseto form hydrocodone benzoic acid enol ester. The reaction may be heatedto between about 80° C. and about 160° C.

In one aspect of this embodiment, the reaction takes place in an organicsolvent. Some suitable organic solvents include but are not limited totoluene, dimethylformamide, N-methyl-2-pyrrolidinone, or xylenes.However, other suitable organic solvents can be used as would be knownin the art. Alternatively, the reaction proceeds without solvent whenusing a base capable of at least partially dissolving hydrocodone freebase and the benzoylating reagent. The base may be, for example,pyridine, N,N-diisopropylethylamine, diazacycloundecene, triethylamine,or potassium benzoate. Various benzoylating agents may be employed. Somenon-limiting examples include benzoic anhydride, benzoyl chloride,benzoyl bromide, N-benzoyloxysuccinimide.

According to another aspect, the hydrocodone benzoic acid enol ester maybe converted to its hydrochloric acid salt. According to thisembodiment, the hydrocodone benzoic acid enol ester is crystallized froman organic solvent in the presence of approximately 1.1 equivalents ofhydrochloric acid.

According to another aspect, a process for making hydrocodone benzoicacid enol ester is provided in which hydrocodone benzoic acid enol estercan be created from hydrocodone and a benzoylating reagent in one step.The possibility to perform this reaction in one step provides anadvantage over prior art methods such as U.S. patent application Ser.No. 12/828,381, which discloses a two-step addition process. The presentone-step method is also robust enough to use crude hydrocodone as astarting material, which provides an advantage over prior art methodsrequiring pure hydrocodone as a starting material.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a chart depicting the inter-relation of hydrocodone benzoicacid enol ester HCl salt crystal forms.

FIG. 2 shows XRPD patterns of pure hydrocodone benzoic acid enol esterHCl salt—(a) Form I and (b) mixture of Forms I and II.

FIG. 3 shows an XRPD pattern of pure hydrocodone benzoic acid enol esterHCl salt Form I.

FIG. 4 shows a DSC of pure hydrocodone benzoic acid enol ester HCl saltForm I.

FIG. 5 shows an XRPD pattern of pure hydrocodone benzoic acid enol esterHCl salt Form II.

FIG. 6 shows a DSC of pure hydrocodone benzoic acid enol ester HCl saltForm II.

FIG. 7 shows an XRPD pattern of pure hydrocodone benzoic acid enol esterHCl salt Form III.

FIG. 8 shows a DSC of pure hydrocodone benzoic acid enol ester HCl saltForm III.

FIG. 9 shows an XRPD pattern of pure hydrocodone benzoic acid enol esterHCl salt Form IV.

FIG. 10 shows a DSC of pure hydrocodone benzoic acid enol ester HCl saltForm IV.

FIG. 11 shows an XRPD pattern of pure hydrocodone benzoic acid enolester HCl salt Form V.

FIG. 12 shows a DSC of pure hydrocodone benzoic acid enol ester HCl saltForm V.

FIG. 13 shows an XRPD pattern of pure amorphous hydrocodone benzoic acidenol ester HCl salt.

FIG. 14 shows a DSC of pure amorphous hydrocodone benzoic acid enolester HCl salt.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

In a first aspect, the present disclosure provides a pharmaceuticallyacceptable salt of hydrocodone benzoic acid enol ester, and processesfor making the pharmaceutically acceptable hydrocodone benzoic acid enolester salt. Prior methods for making hydrocodone benzoic acid enol esterrequired the isolation of pure hydrocodone (through the bitartrate)before preparation of the benzoic acid enol ester. It has been foundthat this purification step is not required. Advantageously, the processof the present disclosure eliminates the purification step therebyproviding a more efficient process of making hydrocodone benzoic acidenol ester, it salts, and various polymorphic forms. Moreover, thepresently described process provides a pure hydrocodone benzoic acidenol ester. For example, a hydrocodone benzoic acid enol ester compoundwith high purity. For the purpose of illustration, the hydrocodonebenzoic acid enol ester can have a level of impurities less than about10% to 0.1% For example, the impurities can be, less than 10% (purity of90%), less than 5% (purity of 95%), less than 2.0% (purity of 98%), lessthan 1.0% (purity of 99%), less than 0.5% (purity of 99.5%), less than0.1% (purity of 99.9%).

Synthesis.

Hydrocodone benzoic acid enol ester hydrochloride may be prepared bydirect treatment of hydrocodone freebase with any benzoylating reagent,while heating the mixture, preferably in the presence of any suitablebase. Hydrocodone benzoic acid enol ester hydrochloride may also beprepared by treatment of hydrocodone HX (X═Cl, Br, HSO₄) salts with anybenzoylating reagent, while heating the mixture in any suitable solventand any suitable base. The Hydrocodone benzoic acid enol ester HCl saltmay then be formed and recrystallized. More specifically, hydrocodone orits salts may be heated in the presence of any benzoylating reagent andany suitable base. Suitable bases include pyridine,N,N-diisopropylethylamine, diazabicycloundecene, triethylamine andpotassium benzoate. Some suitable solvents include toluene,dimethylformamide, N-methyl-2-pyrrolidinone, and xylenes. However, whenusing pyridine or another base capable of at least partially dissolvingboth hydrocodone and the benzoylating reagent, the reaction may beperformed without an additional solvent. Any benzoylating reagent may beused, for example benzoic anhydride or benzoyl chloride.

In one embodiment, the process includes heating crude hydrocodone withbenzoic anhydride and potassium benzoate in toluene or xylenes betweenabout 80° C. and about 160° C. Once complete, the reaction may be workedup using an aqueous extraction to remove excess reagents and salts. Inan alternative aspect of this embodiment, when the appropriate reactionsolvent and anti-solvent are selected according to methods known in theart, the reaction may be cooled and filtered to remove most of thebyproducts and reagents. Hydrocodone benzoic acid enol ester free basemay be isolated in high purity at this stage.

The HCl salt may also be prepared from the filtrate solution andisolated in good purity. Optimally, an anti-solvent is added to thefiltrate. Upon salt formation, hydrocodone benzoic acid enol estercrystallizes from the solution. More specifically, acetone may be usedto dilute the toluene or xylenes filtrate and upon the addition of HCl,crystals of hydrocodone benzoic acid enol ester hydrochloride areobtained. Recrystallization of hydrocodone benzoic acid enol ester HClcan be accomplished from many solvents and solvent/anti-solventcombinations. Some ideal solvents are isopropyl alcohol, acetone andethanol, with or without the addition of suitable anti-solvents.

Hydrocodone benzoic acid enol ester HCl exists in at least 6 distinctsolid forms, designated herein as Forms I-V and amorphous. FIG. 1 is ascheme that depicts the general processes for converting hydrocodonebenzoic acid enol ester HCl between its polymorphic forms I-V. Eachpolymorph has different characteristics, including solubility andstability. For example, the water solubility of Form I at 37° C. wasabout 24 mg/mL while Form II had water solubility of >200 mg/mL-9 timeshigher than the solubility of Form I. Significant water solubilitydifferences between polymorphs could result in variation inbioavailability if mixtures are produced. Therefore, it is important toconsistently produce one polymorph, preferably the one that is morestable.

Recrystallization of hydrocodone benzoic acid enol ester HCl by commonprocedures may produce inconsistencies in the polymorphs produced. Forexample, as shown in FIG. 2, recrystallization of Hydrocodone benzoicacid enol ester HCl using anhydrous isopropanol and isopropyl acetateresults in a mixture comprising a mixture of polymorphs I and II.

The present disclosure describes methods of producing each polymorph insubstantially pure form. Substantially pure means a minimum of 95% ofthe desired polymorph, preferably 98%, and more preferably 99%.

Form I.

A polymorph, designated herein as Form I, may be prepared insubstantially pure form by crystallizing hydrocodone benzoic acid enolester HCl from an organic solvent in the presence of water co-dissolvedin the solvent. The water content of the solvent may vary from traces to100%. More specifically, ethanol containing 1% water may be used as asolvent, with the addition of n-heptane as anti-solvent. Alternativesolvents include but are not limited to alcohols, ethyl acetate, tBME,acetonitrile and acetone. The required water content depends on theproperties of the organic solvent employed.

The XRPD pattern of Form I is presented in FIG. 3. The water content ofForm I is approximately 2% by weight. This corresponds to a hemi-hydratestoichiometry. The DSC of Form I is presented in FIG. 4. Table 1presents selected peak positions from the XRPD and their intensityrelative to the largest peak. A characteristic peak of Form I is at 2θof 9.050. One skilled in the art would realize that the peak positioncould be altered as much as ±0.2° depending on sample preparation methodand XRPD instrument used for data collection.

TABLE 1 Form I XRPD peaks with intensity >10% of the largest peak 2 θ dspacing, A Intensity, % 6.16 14.34 38 9.05 9.77 100 10.95 8.07 31.111.91 7.42 18.8 12.32 7.18 47.7 13.16 6.72 81.8 14.60 6.06 15.6 14.945.92 54.9 17.04 5.20 31.3 17.23 5.14 13.5 17.80 4.98 13.5 18.57 4.7748.6 19.18 4.62 22.4 20.66 4.30 23.9 21.10 4.21 26.6 22.15 4.01 15 23.503.78 15.7 26.07 3.41 20.5 28.39 3.14 10.4

Form II.

A polymorph, designated herein as Form II, may be produced insubstantially pure form by crystallizing any other form of hydrocodonebenzoic acid enol ester HCl from an organic solvent system that issubstantially free of water. Substantially free of water means a watercontent of less than 0.2 percent by volume and more preferably less than0.1 percent by volume. Substantially pure Form II means a minimum of 95%of Form II, or preferably 98% and more preferably 99%.

The XRPD pattern of Form II is presented in FIG. 5. The DSC of Form IIis presented in FIG. 6. Table 2 presents selected peak positions fromthe XRPD and their intensity relative to the biggest peak. Acharacteristic peak of Form II is at 2θ of 4.31°. One skilled in the artwill realize that the peak position may be altered as much as ±0.2°depending on sample preparation method and XRPD instrument used for datacollection.

TABLE 2 Form II XRPD peaks with intensity >1% of the largest peak 2 θ dspacing, A Intensity, % 4.31 20.48 20.6 8.62 10.25 100 12.95 6.83 4.613.19 6.71 4.4 13.42 6.59 2.8 14.33 6.17 2 14.97 5.91 2.4 15.72 5.63 6.617.48 5.07 2.4 18.47 4.80 1.2 21.73 4.09 3.4 22.92 3.88 2.1 24.15 3.68 224.98 3.56 1 26.41 3.37 1.3 26.53 3.36 1.4 26.62 3.34 1.3 27.93 3.19 1.130.46 2.93 1.17

Form III.

A novel polymorph, designated as Form III, may be prepared insubstantially pure form by heating Form I to any temperature between210° C. to 230° C., preferably 215-225° C. and more preferably 217 CC.One skilled in the art could perform this heating operation in adifferent equipment, e.g. a heating cell, while giving enough time atthe high temperature to achieve complete formation of Form II.Substantially pure Form III means a minimum of 95% of Form III, orpreferably 98% and more preferably 99%.

The XRPD pattern of Form III is presented in FIG. 7. The DSC of Form IIIis presented in FIG. 8. Table 3 presents selected peak positions fromthe XRPD and their intensity relative to the largest peak. Acharacteristic peak of Form III is at 2θ of 13.01°. One skilled in theart will realize that the peak position may differ from the listedpositions by as much as ±0.2° depending on sample preparation method andXRPD instrument used for data collection.

TABLE 3 Form III XRPD peaks with intensity >3% of the largest peak 2 θ dspacing, A Intensity, % 4.35 20.28 21.1 8.68 10.18 100 13.01 6.80 8.613.27 6.67 4.7 13.86 6.39 4.1 14.06 6.29 4.5 15.05 5.88 5.6 16.02 5.534.8 18.40 4.82 4.8 21.72 4.09 3.5 22.38 3.97 3.4 26.14 3.41 3.6

Form IV.

A novel polymorph, designated as Form IV, may be prepared insubstantially pure form by exposing Form II to a relative humidity of75-100% for a period of two weeks. Preferably, the relative humidity isin the range of 75-100%, more preferably it is in the range 85-95% andmost preferably the relative humidity is 90%. Substantially pure Form IVmeans a minimum of 95% of Form IV, or preferably 98% and more preferably99%.

The XPRD pattern of Form IV is presented in FIG. 9. The DSC of Form IVis presented in FIG. 10. Table 4 presents selected peak positions in theXRPD and their intensity relative to the largest peak. A characteristicpeak of Form IV is at 2θ of 7.87°. One skilled in the art will realizethat the peak position could be altered as much as ±0.2° depending onsample preparation method and XRPD instrument used for data collection.

TABLE 4 Form IV XRPD peaks with intensity >4% of the largest peak 2 θ dspacing, A Intensity, % 7.87 11.23 100 10.27 8.61 12.1 11.82 7.48 8.112.56 7.04 7.5 13.18 6.71 22.6 14.19 6.24 10.8 14.65 6.04 17.6 15.345.77 5.8 16.77 5.28 6.2 17.67 5.01 4.4 18.58 4.77 9.9 19.50 4.55 5.220.30 4.37 6.2 21.31 4.17 4

Form V.

A novel polymorph, designated as Form V, may be prepared insubstantially pure form by exposing Form III to a relative humidity of75-100% for a period of two weeks. Preferably, the relative humidity isin the range of 75-100%, more preferably it is in the range 85-95% andmost preferably the relative humidity is 90%. Substantially pure Form IImeans a minimum of 95% of Form II, or preferably 98% and more preferably99%.

The XRPD pattern of Form V is presented in FIG. 11. The DSC is presentedin FIG. 12. Table 5 presents selected peak position from the XRPD andtheir intensity relative to the largest peak. A characteristic peak ofForm V is at 2θ of 7.50°. One skilled in the art will realize that thepeak position could be altered as much as ±0.2° depending on samplepreparation method and XRPD instrument used for data collection.

TABLE 5 Form V XRPD peaks with intensity >10% of the largest peak 2 θ dspacing, A Intensity, % 6.17 14.31 21.4 7.50 11.78 100 9.04 9.77 44.210.96 8.07 10.3 11.93 7.42 22.3 12.34 7.17 47 12.64 6.99 12.8 13.13 6.7460.8 14.34 6.17 10.6 14.62 6.05 31.1 14.93 5.93 25 16.73 5.29 17.3 17.045.20 29.8 17.22 5.15 18.6 17.81 4.98 22.4 18.59 4.77 26.4 18.98 4.6713.2 19.19 4.62 18 19.52 4.55 12.4 20.67 4.29 23.4 21.10 4.21 30.6 21.914.05 10.1 22.15 4.01 20.1 22.82 3.89 11.7 23.49 3.78 15.2 25.03 3.5612.5 25.37 3.51 21.9 26.09 3.41 14.6 26.43 3.37 13.8

Amorphous Form.

An amorphous form of hydrocodone benzoic acid enol ester may be preparedin substantially pure form by dissolving the hydrocodone benzoic acidenol ester in an organic solvent, then evaporating the solvent in anoven. The solvent may be any organic solvent that dissolves hydrocodonebenzoic acid enol ester, including methanol, trifluoroethanol, andacetic acid.

The XRPD pattern of the amorphous form is presented in FIG. 13. The DSCof the amorphous form is presented in FIG. 14. Upon heating of amorphoussolid in DSC, an endothermic peak with maximum at about 216° C. wasobserved.

EXAMPLES Example 1: Synthesis of Hydrocodone Benzoic Acid Enol EsterHydrochloride Free Base

A mixture of crude hydrocodone freebase (1 eq.), benzoic anhydride (2.5eq.), and potassium benzoate (1.0 eq.) in toluene (1.8 vol. tohydrocodone) was stirred and heated at 129±3° C. until>98% conversion ofhydrocodone to hydrocodone benzoic acid enol ester by HPLC was achieved(˜24 hr.). The mixture was cooled to room temperature and diluted withtoluene (0.8 vol.) then further cooled to 5° C. The resulting mixturewas filtered to remove potassium benzoate and benzoic acid. The cake waswashed with toluene (2×0.75 vol.). The filtrate was washed with NaHCO₃solution (5%, 4 vol.) and brine (10%, 2 vol.). The organic layer wasdried with sodium sulfate (2×). The mixture was filtered and the cakewas washed with toluene. The filtrate was concentrated to give oilyresidue of hydrocodone benzoic acid enol ester.

Example 2: Synthesis of Hydrocodone Benzoic Acid Enol EsterHydrochloride

A mixture of crude hydrocodone freebase (1 eq.), benzoic anhydride (2.5eq.), and potassium benzoate (1.0 eq.) in toluene (1.8 vol. tohydrocodone) was stirred and heated at 129±3° C. until>98% conversion ofhydrocodone to hydrocodone benzoic acid enol ester by HPLC (˜24 hr.).The mixture was cooled to room temperature and diluted with toluene (0.8vol.) then further cooled to 5° C. The resulting mixture was filtered toremove potassium benzoate and benzoic acid. The cake was washed withtoluene (2×0.75 vol.). The filtrate was diluted with acetone (6 vol.)and cooled to 5±2.5° C. with agitation. Concentrated HCl (1.1±0.05equivalents) was added and the resulting mixture was stirred at 5±2.5°C. for 2 hr. The solid suspension was filtered and the cake was washedwith acetone (2×1 vol.). The solid was dried on the filter to give crudehydrocodone benzoic acid enol ester hydrochloride in 88% yield and 98.9%AUC purity. Crude hydrocodone benzoic acid enol ester was dissolved inethanol (6.0 vol.) at 65 to 70° C. DI water (1% v/v with respect tototal amount of EtOH) was added and the mixture was allowed to cool to50±5° C. and held for 30 to 60 minutes after crystal growth was noticed.n-Heptane (3 vol.) was added at 50±5° C. The mixture was cooled to roomtemperature over approximately 1 hr. and then further cooled to 5±2.5°C. and stirred for 1.5 hr. The solid mixture was filtered and thecrystalline product cake was rinsed with a mixture of ethanol andn-heptane. The cake was dried under vacuum to give hydrocodone benzoicacid enol ester hydrochloride as Form I in 93.5% recovery, >99.9% AUCpurity, 82.5% overall yield from hydrocodone.

Example 3: Synthesis of Hydrocodone Benzoic Acid Enol Ester HC Salt(Form I) from the Corresponding Free Base

To 475 mg of hydrocodone benzoic acid enol ester were added 4.75 mL ofAcetone:Toluene (1.5:1 vol ratio) at room temperature, which resulted ina solution. Then, 1.03 eq. of concentrated HCl (37.5 wt %) were slowlyadded to the freebase solution. Precipitation started during theaddition. After completion of acid addition, the slurry was stirred forabout 30 minutes and filtered. The cake was washed with about 0.5 mLacetone and then dried. The dry solid was substantially pure Form I.

In example 3, other organic solvents such as but not limited toalcohols, tBME and ethyl acetate could be used. Instead of addingsolvent to freebase, the freebase could be added to solvent. Thetemperature of acid addition could be in the range of 0° C. to 60° C.,preferably 10° C. to 40° C. and more preferably 20° C. to 30° C.

Example 4: Form I Recrystallization

To 158 mg of HCl salt Form I was added 7.8 volumes of Ethanol and themixture heated to 65° C. to achieve dissolution. The solution was thencooled to 50° C. followed by addition of 12.2 μL water. When a crystalbed was achieved, 2.7 volumes of heptane were added over about 30minutes followed by cooling to 20-25° C. Filtration and drying resultedin Form I (84% yield) with a chemical purity of 99+%.

In example 4, ethanol could be replaced with other organic solvents suchas but not limited to other alcohols and acetone. Instead of addingsolvent to the salt, the salt could be added to the solvent. Thetemperature of water addition could be in the range of 0° C. to 60° C.,preferably 30° C. to 55° C. and more preferably 45° C. to 50° C. Thewater quantity could be in the range of 0.2% to 15 vol % with respect toorganic solvent, preferably 0.3-5% and more preferably 0.8-1.2%.Alternatively, seeds of Form I could be added to promote crystallizationafter water addition. Heptane volume could be in the range of 0-15volumes, preferably 1-5 volumes and more preferably 2-3 volumes. Thestarting solid of this example could be Form I or any other polymorphsof hydrocodone benzoic acid enol ester HCl.

Example 5: Form I Recrystallization

To 130 mg of HCl salt Form I were added 7.8 volumes of Ethanol andheated to 65° C. to achieve dissolution. The solution was then cooled to50° C. followed by addition of 10 μL water. Within 30 minutes a crystalbed was achieved. The mixture was cooled to 20° C. to 25° C., filtered,and dried which resulted in Form I (80% yield) and a chemical purity of99+%.

In example 5, ethanol could be replaced with other organic solvents suchas but not limited to other alcohols and acetone. Instead of addingsolvent to the salt, the salt could be added to the solvent. Thetemperature of water addition could be in the range of 0° C. to 60° C.,preferably 30° C. to 55° C. and more preferably 45° C. to 50° C. Thewater quantity could be in the range of 0.2% to 15 vol % with respect toorganic solvent, preferably 0.3-5% and more preferably 0.8-1.2%.Alternatively, seeds of Form I could be added to promote crystallizationafter water addition. The starting solid of this example could be Form Ior any other polymorphs of hydrocodone benzoic acid enol ester HCl.

Example 6: Synthesis of Hydrocodone Benzoic Acid Enol Ester HCl Salt(Form II)

To about 118 mg of Form I were added 12.3 volumes of anhydrousisopropanol and 13.4 volumes of anhydrous isopropyl acetate added andthe slurry was heated to reflux to achieve complete dissolution. Thesolution was cooled to about 20° C. over about 3 hrs. Nucleation wasobserved at about 60° C. The slurry was filtered at about 20° C. and theproduct was dried. The resulting solid was substantially pure Form IIwith 67% yield.

Example 7: Synthesis of Hydrocodone Benzoic Acid Enol Ester HC Salt(Form III)

Hydrocodone benzoic acid enol ester HCl salt (Form I) was heated to 217°C. in DSC followed by cooling to room temperature which resulted insubstantially pure Form III by XRPD analysis.

Example 8: Synthesis of Hydrocodone Benzoic Acid Enol Ester HCl Salt(Form IV)

Hydrocodone benzoic acid enol ester HCl salt (Form II) was exposed tohumidity of more than 90% at room temperature for two weeks, whichresulted in Form IV confirmed by XRPD.

Example 9: Synthesis of Hydrocodone Benzoic Acid Enol Ester HCl Salt(Form V)

Hydrocodone benzoic acid enol ester HCl salt (Form III) was exposed tohumidity of more than 90% at room temperature for two weeks, whichresulted in Form V confirmed by XRPD.

Example 10: Synthesis of Hydrocodone Benzoic Acid Enol Ester HCl Salt(Amorphous Form)

64 mg of Hydrocodone benzoic acid enol ester HCl salt was dissolved in 1mL of methanol. The solvent was evaporated in the oven temperature of50° C. and under vacuum. The resulting solid was amorphous by XRPD.

Example 11: Slurry Stability Studies

A number of experiments were performed to map out the relative stabilityof Forms I to V. Prior to the relative stability tests, the solids ofForms I, II and III were dried in the oven to remove surface water.Table 6 shows the results of these slurries. It was found that Form I isalways the most stable in water or organic solvents that contain water.However, in anhydrous organic solvents, Form II is the more stable one,especially at higher temperatures. Therefore, Form I was selected as themost viable form for development.

TABLE 6 Relative stability of various forms Starting After 1 day slurryAfter 10 days slurry Solvent Form 25° C. 50° C. 25° C. 50° C. Water I +II + III I I I I Water I + IV + V I I I I IPA I + II + III I + II I + III II Acetonitrile I + II + III I + traces II I I of II

Example 12: Grinding Stability Studies

Form I was exposed to dry and solvent drop grinding using mortar andpestle. This test mimics shear stresses that a crystal polymorph couldbe exposed to during commercial formulation. Table 7 illustrates thegrinding results.

TABLE 7 Wet and dry grinding of Form I - 5 minutes of manual grindingStarting Form Conditions Resulting Form I Dry grinding I I Wetgrinding-~0.3X vol I water I Wet grinding-~0.5X vol IPA I

Example 13: Humidity Stability Studies

The stability of various forms of hydrocodone benzoic acid enol esterhydrochloride was evaluated under high humidity (RH>90% at roomtemperature) conditions. Form I was stable for at least two weeks. FormII was hygroscopic and unstable, and converted to Form IV. Form III washygroscopic and unstable, and converted to Form V.

1-83. (canceled)
 84. A compound comprising a polymorphic form ofhydrocodone benzoic acid enol ester hydrochloride, wherein thepolymorphic form is Form I, wherein Form I has an x-ray powderdiffraction pattern comprising peaks at about the following 2θ values:9.05, 12.32, 13.16, 14.94, and 18.57.
 85. The compound of claim 84,wherein Form I has an x-ray powder diffraction pattern furthercomprising peaks at about the following 2θ values: 6.16, 10.95, 11.91,14.60, 17.04, 17.23, 17.80, 19.18, 20.66, 21.10, 22.15, 23.50, 26.07,and 28.39.
 86. A solid pharmaceutical composition comprising atherapeutically effective amount of a polymorphic form of hydrocodonebenzoic acid enol ester hydrochloride and a pharmaceutically acceptableexcipient in a formulation for oral administration, wherein thepolymorphic form is Form I, wherein Form I has an x-ray powderdiffraction pattern comprising peaks at about the following 2θ values:9.05, 12.32, 13.16, 14.94, and 18.57.
 87. The solid pharmaceuticalcomposition of claim 86, wherein Form I has an x-ray powder diffractionpattern further comprising peaks at about the following 2θ values: 6.16,10.95, 11.91, 14.60, 17.04, 17.23, 17.80, 19.18, 20.66, 21.10, 22.15,23.50, 26.07, and 28.39.
 88. A method for treating pain in a patientcomprising the step of selecting a patient that is in need of paintreatment, administering to said patient a pharmaceutical compositioncomprising a therapeutically effective amount of one or more polymorphicforms of hydrocodone benzoic acid enol ester hydrochloride the compoundof claim
 84. 89. A method for treating pain in a patient comprising thestep of selecting a patient that is in need of pain treatment,administering to said patient a pharmaceutical composition comprising atherapeutically effective amount of one or more polymorphic forms ofhydrocodone benzoic acid enol ester hydrochloride the compound of claim86.
 90. A process for preparing a polymorphic form of hydrocodonebenzoic acid enol ester hydrochloride, the process comprisingrecrystallizing hydrocodone benzoic acid enol ester hydrochloride froman organic solvent containing less than 0.2% water, wherein thepolymorphic form is Form I-Form V.